Prescriber UpdateVol. 37 No. 3 September 2016

ISSN 1172-5648 (print) ISSN 1179-075X (online)

www.medsafe.govt.nz

The Medsafe Files – Episode One: What is Medsafe? 34

Switching Antidepressants – Careful Management Required 35

Quarterly Summary of Recent Safety Communications 35

Reminder: Hyperkalaemia caused by Spironolactone and Renin-angiotensin System Medicine Interactions 36

Can I Take St John’s Wort with Other Medicines? 36

Drug-induced Gynaecomastia 37

Posaconazole (Noxafil) – Tablets and Suspension are not Interchangeable 38

Prescriber Update Survey – The Results are In! 39

Dangers of Purchasing Online Medicines (Operation PANGEA IX) 39

About the Medication Error Reporting Programme 40

Soya-based Excipients – a Problem for People with Peanut Allergy? 42

Medicines Monitoring 43

Beta-lactam Antibiotics and Cross-reactivity 44

Medicines can Impair Driving 45

MARC’s Remarks: June 2016 Meeting 46

New Medicine Approvals 47

Contents

34 Prescriber Update 2016; 37(3) September

The Medsafe Files – Episode One: What is Medsafe?Key Messages

z Medsafe is the medicines and medical devices regulator for New Zealand.

z Our role is to administer the New Zealand legislation to help industry and healthcare professionals comply with the law.

z The pre-marketing approval process of medicines and the post-marketing surveillance of medicines and medical devices are activities we undertake to manage the risks associated with the use of medicines and medical devices.

z Ultimately, the aim is to maintain a favourable balance between the benefits and risks of harm of using a therapeutic product in the intended treatment population.

Responses to consultations and enquiries to Medsafe demonstrate that our role is not always fully understood. Additionally, new legislation is on the way and it is important for you to understand our role so you can contribute to consultation. Welcome to our new series of articles ‘The Medsafe Files’.

Medicines legislation is in place to manage the risks of avoidable harm associated with the use of therapeutic products. Medsafe is the New Zealand Medicines and Medical Devices Safety Authority and, with some exceptions such as pharmacy licensing, is responsible for administering the Medicines Act 1981 and Medicines Regulations 1984.

The role of Medsafe as the regulator is to administer the New Zealand legislation to help industry and healthcare professionals comply with the law. The aim is to maintain a favourable balance between the benefits and risks of harm of using a therapeutic product in the intended treatment population. We undertake activities such as the pre-marketing approval process of medicines and post-marketing surveillance of

medicines and medical devices to manage the risks associated with the use of medicines and medical devices.

Medsafe regulates products that are used for a therapeutic purpose including medicines, related products, medical devices and controlled drugs used as medicines. Definitions for these product types are on the Medsafe website (www.medsafe.govt.nz/other/about.asp#do).

Medsafe is accountable to the Ministry of Health and, through the Ministry, to the Minister of Health. Medsafe is largely funded by fees collected from the therapeutics industry. Medsafe is small by international standards, with 56 full-time staff based in both Auckland and Wellington. In comparison, the Therapeutic Goods Administration, the equivalent organisation in Australia, employs around 750 staff.

Medsafe is not involved in funding medicines; this is the responsibility of PHARMAC (www.pharmac.govt.nz/). Medsafe does not regulate healthcare professional practice and Medsafe cannot provide medical advice about an individual’s medical condition. We encourage consumers to talk to their healthcare professional if they have concerns about a medicine they are taking.

Upcoming episodes of The Medsafe Files include the following:

� clinical trials

� pre-market approval

� devices

� pharmacovigilance

� border control

� good manufacturing practice

� classification.

See www.medsafe.govt.nz/other/about.asp for more information about Medsafe.

The Medicines Act 1981 and the Medicines Regulations 1984 is at www.legislation.govt.nz

Prescriber Update 2016; 37(3) September 35

Switching Antidepressants – Careful Management RequiredThe Centre for Adverse Reactions Monitoring (CARM) recently received a report of a patient who experienced severe withdrawal symptoms within 72 hours of stopping paroxetine1. These symptoms, which included dizziness, vertigo, confusion, paraesthesia and excessive dreaming, affected their ability to drive and attend work. The patient had been advised to stop taking paroxetine five days prior to commencing a new antidepressant.

Healthcare professionals are reminded that careful management is required when switching antidepressants to reduce the risk of serotonin syndrome, hypertensive crisis or withdrawal syndrome2.

When managing a switch, refer to the New Zealand Formulary table on switching

antidepressants (http://nzf.org.nz/nzf/resource/Antidepressant_Switching_Table.pdf). The table provides general guidance on how to safely and effectively switch between antidepressants2. Further information regarding switching antidepressants can be found in individual medicine data sheets, available on the Medsafe website (www.medsafe.govt.nz/profs/datasheet/DSForm.asp).

Please continue to report any adverse reactions to CARM. Reports can be submitted on paper or electronically (https://nzphvc.otago.ac.nz/).

References1. CARM case ID 119445. URL: www.medsafe.govt.nz/

Projects/B1/adrsearch.asp2. New Zealand Formulary. 2016. Antidepressant drugs.

NZF v45. URL: www.nzf.org.nz/nzf_2225 (accessed 23 February 2016).

Quarterly Summary of Recent Safety Communications

The early warning system provides current and historical information on safety concerns for medicines and medical devices. These warnings are intended to help consumers and healthcare professionals make informed decisions about their use of medicines and medical devices.

More information about the early warning system can be found on the Medsafe website (www.medsafe.govt.nz/Projects/B2/EWS.asp).

Consumer information leaflets provide information about medicines and medical devices or medical conditions to consumers.

Date Communication Topic

6 July 2016 Consumer Information Can I take St John’s wort with other medicines?

21 June 2016 Media Release Medsafe Warns of the Dangers of Purchasing Medicines Over the Internet

30 May 2016 Consumer Information The Pros and Cons of Taking Statins

26 May 2016 Monitoring Rivaroxaban, dabigatran and apixaban and possible risk of hair loss (alopecia) added to the Medicines Monitoring scheme

26 May 2016 Monitoring Apex e-chamber spacer device - user issues with valve and round mouthpiece

If you would like to receive Medsafe’s early warning communications you can subscribe at www.medsafe.govt.nz/profs/subscribe.asp

36 Prescriber Update 2016; 37(3) September

Reminder: Hyperkalaemia caused by Spironolactone and Renin-angiotensin System Medicine Interactions

Key Messages

z The risk of severe hyperkalaemia needs to be considered with the concomitant use of spironolactone and angiotensin-converting enzyme inhibitors (ACEis) or angiotensin receptor blockers (ARBs), particularly in patients with renal impairment.

z Use the lowest effective doses of spironolactone and ACEis or ARBs if co-administration is required.

z Potassium levels and renal function should be regularly monitored.

z Treatment should be discontinued or temporarily withheld if hyperkalaemia occurs.

The United Kingdom’s medicines regulator (Medicines and Healthcare products Regulatory Agency or MHRA) has recently noted an increase in reports of hyperkalaemia due to the use of spironolactone with angiotensin-converting enzyme inhibitors (ACEis) or angiotensin receptor blockers (ARBs)1.

In New Zealand, the Centre for Adverse Reactions Monitoring (CARM) has received five cases of hyperkalaemia when an ACEi or an ARB was co-administered with spironolactone in the last 12 years.

Spironolactone is a potassium-sparing diuretic indicated for a number of conditions including essential hypertension and congestive heart

failure2,3. ACEis and ARBs can also reduce the loss of potassium via the kidneys and are often used in the management of patients with heart disease and hypertension3.

The risk of severe hyperkalaemia needs to be considered with the concomitant use of spironolactone and ACEis or ARBs, particularly in patients with renal impairment. Use the lowest effective doses of spironolactone and ACEis or ARBs if co-administration is required1.

Serum potassium levels and renal function should be monitored regularly after initiation of spironolactone, an ACEi or an ARB, and again when increasing the dose2,3. Treatment with spironolactone should be discontinued or temporarily withheld in hyperkalaemic patients2.

Further information on medicines known to increase serum potassium levels can be found in a previous edition of Prescriber Update (www.medsafe.govt.nz/profs/PUArticles/Sep2015/Medicines&Hyperkalaemia.htm).

References1. Medicines and Healthcare products Regulatory Agency.

2016. Spironolactone and renin-angiotensin system drugs in heart failure: risk of potentially fatal hyperkalaemia. 17 February 2016. URL: www.gov.uk/drug-safety-update/spironolactone-and-renin-angiotensin-system-drugs-in-heart-failure-risk-of-potentially-fatal-hyperkalaemia (accessed 17 June 2016).

2. Mylan New Zealand Limited. 2013. Spiractin Data Sheet 26 November 2013. URL: www.medsafe.govt.nz/profs/datasheet/s/Spirotonetab.pdf (accessed 16 June 2016).

3. Best Practice Advocacy Centre. 2013. Managing patients with heart failure in primary care. February 2013. URL: www.bpac.org.nz/BPJ/2013/february/managing-heart-failure.aspx (accessed 16 June 2016).

Can I Take St John’s Wort with Other Medicines?Medsafe recently published an information leaflet to help consumers understand whether they can take other medicines with St John’s wort.

The leaflet provides information about St John’s wort including:

� how St John’s wort affects medicines

� which medicines can be affected

� what to look out for if taking St John’s wort.

The leaflet is available on the Medsafe website ( w w w. m e d s a f e . g ov t . n z /C o n s u m e r s/educational-material/St%20John’s%20Wort%20July%202016.pdf).

Prescriber Update 2016; 37(3) September 37

Drug-induced Gynaecomastia

Key Messages

z Medicines cause 10% to 25% of all cases of gynaecomastia.

z Consider the possibility of a medicine-related cause in male patients who develop gynaecomastia, even if the medicine has been taken for some time.

z Gynaecomastia may persist after the causal medicine has been discontinued.

A recent report to the Centre for Adverse Reactions Monitoring (CARM) described a male patient who developed bilateral gynaecomastia after taking omeprazole (20 mg twice a day) for 10 years1.

Gynaecomastia is a benign proliferation of male breast glandular tissue caused by an imbalance between the actions of oestrogens relative to the actions of androgens on breast tissue2–6.

Medicines have been estimated to cause 10% to 25% of all cases of gynaecomastia2,4,5.

DiagnosisIn male patients proliferation of breast tissue may be due to gynaecomastia, pseudo-gynaecomastia or breast cancer. A physical examination is necessary to distinguish the cause2–5. Breast imaging and ultrasonography may be considered if breast cancer is suspected2,3,5.

Once gynaecomastia is confirmed, consider reversible causes including medicines and over-the-counter products (see Causal Medicines)2–6.

In patients with no apparent cause of gynaecomastia, laboratory tests may be useful. Tests may include liver, renal and thyroid

function2–5. A limited hormonal work-up (eg, testosterone, oestradiol, LH, FSH, hCG, and prolactin) may be useful to detect hormonal imbalances2–5.

Causal MedicinesMedicines may cause gynaecomastia through a number of mechanisms including:4,5

� increased serum oestrogen levels or oestrogen-like activity

� decreased testosterone levels

� hypogonadism

� anti-androgenic effects

� increased prolactin levels.

Many commonly prescribed medicines have been reported to cause gynaecomastia5. Table 1 provides examples of medicines that have been associated with gynaecomastia2,3.

Other reported non-medicine causes of gynaecomastia include alcohol, amphetamines, heroin, marijuana (cannabis) and phytoestrogens (in some herbal medicines)2,3,4,7.

New Zealand CasesUp to 30 June 2016, 124 reports of gynaecomastia suspected to be caused by medicines have been reported to CARM (4.8% of reports were in women). These reports involved 135 suspected medicines as more than one medicine was described in some reports. The average age in these reports was 58 years.

The 10 most frequently reported medicines are summarised in Figure 1. These medicines comprise 65% of total reports. Of these (n=81), time to onset was reported in 67 reports. In six reports, the onset was reported to have occurred

Table 1: Medicines reported to be associated with gynaecomastia [this is not an exhaustive list]2–7

Quality of Evidence* Examples of Medicines and/or Medicine Classes

Good Bicalutamide, cyproterone, dutasteride, finasteride, flutamide, goserelin, ketoconazole, leuprorelin, oestrogens, spironolactone

Fair Alkylating agents, anabolic steroids, efavirenz, nifedipine, omeprazole, opioids, risperidone, verapamil

*Classification of quality of evidence for strength of medicine associations with gynaecomastia. Good: Systematic review of randomised controlled trials, randomised placebo controlled trial, or prospective cohort studies with or without concurrent controls plus good pathophysiological explanation. Fair: Retrospective studies, case-control studies or case series with good pathophysiological explanation.

38 Prescriber Update 2016; 37(3) September

within one month and in 61 reports, the onset was reported to be one year or longer.

Figure 1: Top 10 medicines associated with gynaecomastia in the CARM database (number of reports)

SpironolactoneOmeprazoleCimetidineRanitidineRisperidone

SimvastatinDigoxinAtorvastatinFinasterideMethyldopa

7

6

3 3

7

7

7 10

28

3

ManagementIf medicine-induced gynaecomastia is suspected, the medicine should be withdrawn or discontinued if possible2,4. Switching to a medicine of the same class, but with a lower association with gynaecomastia may prevent re-emergence of gynaecomastia2.

Within one month of discontinuing the causal medicine, a reduction in tenderness and softening of the glandular breast tissue should occur. However, if the gynaecomastia has been present for more than one year, the presence of fibrosis may mean that surgery is required2–6.

Please continue to report any adverse reactions to CARM. Reports can be submitted on paper or electronically (https://nzphvc.otago.ac.nz/).

References1. CARM case ID 119664. URL: www.medsafe.govt.nz/

Projects/B1/adrsearch.asp2. Deepinfer F, Braunstein GD. 2012. Drug-induced

gynecomastia: an evidence-based review. Expert Opinion on Drug Safety 11(5): 779–795.

3. Braunstein GD. 2007. Gynecomastia. The New England Journal of Medicine 357: 1229–1237.

4. Eckman A, Dobs A. 2008. Drug-induced gynecomastia. Expert Opinion on Drug Safety 7(6): 691–702.

5. Narula HS, Carlson HE. 2014. Gynaecomastia – pathophysiology, diagnosis and treatment. Nature Reviews Endocrinology 10: 684–698.

6. Carlson HE. 2011. Approach to the Patient with Gynecomastia. The Journal of Clinical Endocrinology & Metabolism 96: 15–21.

7. Bowman JD, Kim H, Bustamante JJ. 2012. Drug-Induced Gynecomastia. Pharmacotherapy 32(12): 1123–1140.

Posaconazole (Noxafil) – Tablets and Suspension are not InterchangeablePosaconazole (Noxafil) is a broad-spectrum triazole antifungal, available as both a modified release tablet and oral suspension.

Healthcare professionals are reminded that the two formulations are not interchangeable due to a difference in dosing of each formulation1.

Medication errors have resulted from substitutions of the tablets and oral suspension. The European Medicine Agency (EMA) recently reported that some patients have mistakenly received oral suspension instead of tablets, leading to underdosing2. The EMA also reports that patients have received tablets instead of the suspension, leading to overdose and side effects2.

Further information is available on the medicine data sheet (www.medsafe.govt.nz/profs/datasheet/n/Noxafilsusp.pdf).

References1. Merck Sharp & Dohme New Zealand Limited. 2015. Noxafil

Data Sheet 16 October 2015. URL: www.medsafe.govt.nz/profs/datasheet/n/Noxafilsusp.pdf (accessed 20 July 2016).

2. European Medicines Agency (EMA). 2016. EMA warns that Noxafil tablets and oral suspension have different doses and are not interchangeable 24 June 2016. URL: www.ema.europa.eu/ema/index.jsp?curl=pages/news_and_events/news/2016/06/news_detail_002557.jsp&mid=WC0b01ac058004d5c1 (accessed 20 July 2016).

Prescriber Update 2016; 37(3) September 39

Prescriber Update Survey –– The Results are In!The Prescriber Update survey ran between 3 March and 8 April 2016. This was your chance to give your feedback and help us improve Prescriber Update.

Three-hundred and fifty-two readers participated in the survey. We estimate that this is 8.5% of individuals subscribed to receive Prescriber Update through electronic subscription or 2.3% of the total number of recipients.

Participants included pharmacists (34.1%), doctors (25.3%) and nurses (19.9%).

Prescriber Update was rated as relevant (54.3%) or somewhat relevant (37.7%) to the work of the respondents.

Prescriber Update is read from cover-to-cover by one-third (33.1%) of respondents. Twenty percent of respondents only read the key messages. Around half (52.7%) of respondents like the current publication frequency (three monthly). Most respondents (70%) were satisfied or very satisfied with the current format of Prescriber Update.

Some changes to Prescriber Update were proposed in the survey.

� Inclusion of a short summary (one to two sentences) of each article on the cover page was rated useful by 44% of respondents.

� The use of pictures and/or photos where relevant was endorsed by 25% of respondents.

Articles that readers would like to see more of include the following.

� Reviews about the safety of a specific medicine or class of medicine.

� Safety briefings reporting on a specific medicine and adverse reaction.

� Occasional spotlight on a particular therapeutic class or class of medicine.

� Information on new medicines.

Medsafe would like to thank everyone who took the time to participate in the survey. We are taking your feedback into consideration; look out for some changes in the near future!

Read the summary report on the survey at www.medsafe.govt.nz/profs/PUArticles/ReaderSatisfactionSurveyOutcomeReport July2016.pdf

Dangers of Purchasing Online Medicines (Operation PANGEA IX)Medsafe recently participated with New Zealand Customs in the annual international initiative known as Operation PANGEA, to highlight the illicit trade in medicines around the world. The results highlight the continuing importation of potentially substandard medicines into New Zealand.

Operation PANGEA IX was an International Internet Week of Action led by INTERPOL (30 May to 7 June 2016) involving 103 countries. It feeds data from the ongoing New Zealand border control programme into the worldwide effort aimed at disrupting criminal networks trading in illegal counterfeit and poor quality medicines.

As a result of Operation PANGEA IX, 173 packages were held requiring further investigation, slightly less than last year.

These parcels originated from 31 countries around the world and were stopped because

they contained prescription medicines, were not labelled or were known to contain undeclared or hidden ingredients. The most common sources of these products were India (84), China (14) and the United Kingdom (14).

Medicines for erectile dysfunction were the most common products examined by Medsafe (3652 individual tablets). Medicines for the treatment of infections, heart disease and pain were the next most prevalent.

Medicines purchased online present a risk to consumers because their quality, safety and effectiveness cannot be guaranteed and they may not be appropriate for the intended recipient.

It is important to stress that although a website may seem to be legitimate and established in a well-regulated country, this may not always be the case.

40 Prescriber Update 2016; 37(3) September

Medsafe routinely receives packages from New Zealand Customs that are suspected to contain medicines, with thousands of interceptions each year being referred for assessment.

Prescription medicines are referred to Medsafe by New Zealand Customs to ensure compliance with New Zealand law. Most prescription medicines Medsafe detains are held until the person importing them provides a valid authorisation from their doctor indicating that it is acceptable for them to use the medicine. If this does not occur the medicines are destroyed.

Healthcare professionals can help reduce the number of fake and adulterated medicines that enter New Zealand by doing the following.

1. Be wary if a patient requests a prescription for a medicine purchased over the internet. Criminals go to great lengths to make their websites appear genuine. It is common for online businesses to purport to be reputable online pharmacies when they are not. Some pretend to be located in New Zealand.

2. Consider the following questions before providing a prescription for a medicine obtained from an online business.

– Is the patient under your care?

– Is the medicine, dose and quantity appropriate for the patient?

– Is the patient aware of the risks of using medicines purchased over the internet?

– Are you willing to take responsibility for prescribing your patient an unapproved medicine that is likely to be of unknown quality and origin?

– Are you satisfied that your actions will meet ethical standards?

3. If a patient presents with unexplained symptoms after taking any medicines or dietary supplements, consider that the patient may have used a medicine or dietary supplement purchased over the internet.

4. Report adverse reactions to the Centre for Adverse Reactions Monitoring (CARM). Reports can be submitted on paper or electronically (https://nzphvc.otago.ac.nz/).

5. Report any suspicions you have that a product is substandard, adulterated or fake to Medsafe (recalls@moh.govt.nz).

For more information on Operation PANGEA IX visit www.interpol.int/News-and-media/News/2016/N2016-076

About the Medication Error Reporting Programme

Key Messages

z The Medication Error Reporting Programme (MERP) is operated by the New Zealand Pharmacovigilance Centre.

z The MERP collects reports of errors to supplement, contribute to and improve the safe use of medicines.

z The MERP is an online, national, voluntary, no-blame reporting system.

z Reports to the MERP are utilised to inform and drive national medication safety initiatives.

Medication errors are unintentional errors in the use of a medicine. Errors may arise at any stage of medicine use; prescribing, dispensing, administration and monitoring. Errors include those of commission (where an error occurs as a result of an action taken) and those of omission

(where an error occurs as a result of an action not taken). Medication errors occur across all healthcare settings. Fortunately, most errors are detected and corrected before reaching the patient. However, some errors are not and may result in serious patient harm.

The Medication Error Reporting Programme (MERP) is an initiative of the New Zealand Pharmacovigilance Centre (NZPhvC) and operates alongside the Centre for Adverse Reactions Monitoring (CARM). The MERP aims to improve the safe use of medicines for New Zealanders.

The MERP is an online, national, voluntary, no-blame reporting system for primary care, where reports can be made anonymously if preferred. Voluntary reporting of actual and ‘near miss’ errors can help to identify hazards and risks. This information highlights vulnerabilities in systems that can be targeted for improvement to reduce the risk of harm to patients.

Prescriber Update 2016; 37(3) September 41

Importance of the MERP and synergy with CARMBeyond local systems for managing medication errors, sharing events with the NZPhvC contributes to a national database of events which:

� complements the CARM programme, as harms from medicines may arise not only from adverse reactions but also errors in use

� helps identify rare events that may otherwise go unrecognised

� provides timely insights into New Zealand-specific error trends and patterns over time

� informs national medication safety initiatives.

How reporting to the MERP helps toward improving medication safety in New ZealandThe NZPhvC works with the Health Quality & Safety Commission (the Commission) to improve medication safety in New Zealand. Reports to the MERP are utilised to inform and drive national initiatives through a continual process involving reporting, analysis, solution development and systems change as shown in Figure 1.

Who can report to the MERP? � Any healthcare professional can report a

primary care medication error electronically (https://nzphvc.otago.ac.nz/merp/report/).

� Organisations who collate data on medication errors can contribute to the MERP. Please email merpnz@otago.ac.nz for further information.

Reporting Voluntary reports

to NZPhvC

Analysis by NZPhvC

Solution development

by the Commission’s Medication Safety Expert

Advisory Group

Shared learning Systems change

In partnership with the Commission and other

stakeholders

What to report to the MERPActual and ‘near miss’ errors pertaining to prescribing, product labelling/packaging/names, compounding, dispensing, distribution, administration and monitoring. Reports of ‘near misses’ or unsafe situations that could lead to patient harm are encouraged as this allows a more proactive approach to prevention.

Reporting of errors covers all types of medicines, vaccines, as well as complementary and herbal remedies, but excludes blood products.

Report a suspected medicine-related reaction, error or safety problem to the NZPhvC:

Figure 1: The MERP national reporting and learning system for primary care

Errors in the use of a medicine, vaccine or related product (including ‘near misses’ and potential safety problems) https://nzphvc.otago.ac.nz/merp/report/

Suspected adverse reactions to a medicine, vaccine or related product https://nzphvc.otago.ac.nz/report/

If unsure, please report to CARM or phone for advice 0800 4MONITOR (0800 466648).

42 Prescriber Update 2016; 37(3) September

Soya-based Excipients – a Problem for People with Peanut Allergy?

Key Messages

z A few people with peanut allergy are also allergic to soya.

z Soya and peanut (arachis) oils are sometimes used as excipients in medicines.

z No safe level for residual protein in soya or peanut oils has been established for allergic people.

z Pharmaceutical companie s are encouraged to follow European guidelines for these excipients and to alert healthcare professionals and patients when medicines contain soya and/or peanut oil.

Peanuts are the seed of the legume Arachis hypogaea1. The prevalence of peanut allergy is estimated at about 1% of the population2. Peanut allergy causes more concern than most other food allergies as it is more severe and more persistent3.

Soyabeans are the seed of the legume Glycine max. Soya allergy usually manifests in childhood. The prevalence in adults is poorly described, but has been estimated at around 0.4%3. Isolated soya allergy seems to be rare; 88% of children with soya allergies also have peanut allergies3. Allergic symptoms to soya include atopic dermatitis and enterocolitis3. Anaphylaxis caused by soya is very rare. It has been postulated that the presence of anti-inflammatory chemicals in soya may reduce the allergic response3. In the few cases where death was reported after ingestion of soya the patients also had severe peanut allergies3.

Food induced allergenic reactions can be classified into two groups according to the type of immune reaction4.

� Immunoglobulin E (IgE) mediated symptoms (includes anaphylaxis).

� Non-IgE mediated gastrointestinal symptoms; these reach a peak approximately 48 hours after ingestion.

Several methods have been used for diagnosing suspected food allergy4.

� Skin prick testing; gives a large number of false positive results and shows sensitisation rather than allergy.

� Food-specific IgE measured by ELISA or immunoblotting.

� Double blind placebo controlled food challenge.

� Skin patch testing.

� Basophil activation test.

The results of some of these tests show only that a person is sensitised to an allergen, but is not necessarily allergic.

Cross-reactivity is less common than cross-sensitisation. Cross-sensitisation generally implies a positive skin test or IgE test but the patient is clinically tolerant, whereas a cross-reactivity implies that clinical symptoms are experienced5.

Cross-reactivity relies on the presence of conserved anti-body accessible surface structures of proteins and is often observed between members of the same protein family1. Plants in the same genus such as legumes are likely to have similar proteins.

Peanuts contain 12 known allergens which are categorised into six families:1,2

� the cupin superfamily (Ara h 1, 3)

� the prolamin superfamily (Ara h 2, 6, 7, 9)

� the profilin family (Ara h 5)

� bet v-1-related proteins (Ara h 8)

� oleosin/glycosyl transferase GT-C (Ara h 10, 11)

� defensin/scorpion toxin-like knottin (Ara h 12, 13).

The peanut allergens Ara h 8, 5 and 9 are responsible for allergic cross-reactivity across a wide variety of unrelated plants and are considered to be panallergens1.

Several soya allergens share high sequence homology to their counterparts in peanut. Soya Gly m 5 (ß-conglycinin, 7 S) is close to Ara h 1. Ara h 3 and soyabean Gly m 6 (glycinin, 11 S) share a similar 3D structure1.

Approximately 50% of peanut-allergic patients have positive skin prick tests to other legumes, but less than 5% are clinically symptomatic upon ingestion of legumes2,5.

Peanut allergic people have a high theoretical risk of cross-reactivity to soyabean but double-blinded food challenges have shown a low rate of cross-reaction4. In a group of 39 peanut sensitised patients, 33 (87%) were also sensitised to soyabean and 11 (33%) reported symptoms to a wide variety of soya products1. In a study of 32 children with

Prescriber Update 2016; 37(3) September 43

peanut allergy, 10 (31%) had a positive skin test to soya whilst one (3%) had a clinical reaction5.

In a study investigating factors associated with the development of peanut allergy in childhood, consumption of soya was independently associated with peanut allergy6.

Refined soya and peanut oil contain low quantities of allergenic protein, depending on the refining process. No safe level for these residual proteins has been established. Neither is it clear that long-term consumption of medicines containing these oils will not induce allergy7,8.

Whilst the risk appears to be low, the European Medicines Agency (EMA) has taken a precautionary approach in their guidelines on excipients7,8. The EMA guideline recommends that medicinal products containing soya oil should include a contraindication for patients allergic to peanut or soya. In New Zealand, pharmaceutical companies are encouraged to follow this guidance, particularly if the allergenic potential of the peanut or soya based excipient has not been characterised.

References1. Bublin M, Breiteneder H. 2014. Cross-reactivity of peanut

allergens. Current Allergy Asthma Reports 14: 426.

2. Mueller GA, Maleki SJ, Pedersen LC. 2014. The molecular basis of peanut allergy. Current Allergy Asthma Reports 14: 429.

3. Masilamani M, Commins S, Shreffler W. 2012. Determinants of food allergy. Immunology and Allergy Clinics of North America 32: 11–33.

4. Verma AK, Kumar S, Das M, et al. 2013. A comprehensive review of legume allergy. Clinical Reviews in Allergy & Immunology 45: 30–46.

5. Kazatsky AM, Wood RA. 2016. Classification of food allergens and cross-reactivity. Current Allergy Asthma Reports 16: 22.

6. Lack G, Fox D, Northstone K, et al. 2003. Factors associated with the development of peanut allergy in childhood. The New England Journal of Medicine 348: 977–985.

7. European Medicines Agency (EMA). 2003. Medicinal products for human use; Safety, environment and information; Excipients in the label and package leaflet of medicinal products for human use. Volume 3B. URL: www.ema.europa.eu/docs/en_GB/document_library/Scientific_guideline/2009/09/WC500003412.pdf (accessed 14 July 2016).

8. European Medicines Agency (EMA): Committee on Herbal Medicinal Products (HMPC). 2006. Public Statement on the Allergic Potency of Herbal Medicinal Products Containing Soya or Peanut Protein. 12 January 2006. URL: www.ema.europa.eu/docs/en_GB/document_library/Scientific_guideline/2010/04/WC500089954.pdf (accessed 14 July 2016).

WE NEED YOUR HELP!Please send your reports for these potential safety issues* listed in the table below.

Medicine Potential Safety Issue Active Monitoring Ends

Ticagrelor Depression, Suicidality 30 September 2016Rivaroxaban, Dabigatran, Apixaban

Hair loss (Alopecia) 31 December 2016

• is a Medsafe scheme designed to collect more information on potential safety signals for specific medicines.

• Safety signals are identified from reports of adverse medicine reactions sent to the Centre for Adverse Reactions Monitoring (CARM). For further information see the Medsafe website.

• The scheme does not replace routine adverse reaction reporting. Find out how to report at: www.otago.ac.nz/carm or www.medsafe.govt.nz

Reporting form for Adverse Reactionsto Medicines, Vaccines and Devices

and all Clinical Events for IMMP

Surname: First Name/s:

Address:

ALL MEDICINES IN USE *ASTERISK SUSPECT MEDICINE/S* Include over-the-counter (OTC) and alternative medicines

Medicine or Vaccine+batch no. Daily Dose Route Date Started Date Stopped Reason for Use (and brand name if known)

DESCRIPTION OF ADVERSE REACTION OR EVENT

Date of onset:

Recovered Not yet recovered but improved Not yet recovered Unknown Fatal - Date of Death:

Severe? - Yes No Rechallenged? - No Yes Result:

OTHER FACTORS - Please tick or specify as appropriate

Renal disease Allergy : Other Medical Conditions:

Hepatic disease Nutritional Suppl or OTC use : Industrial Chemicals :

REPORTER - Please tick as appropriate: Doctor Pharmacist Dentist Nurse Other :

Name:

Address: Signature:

Phone: Date:

Send completed form to CARMFreepost 112002, CARM, PO Box 913, Dunedin 9054 or Fax: (03) 479 7150

NHI No:

Date of Birth:

Ethnicity:

PATIENT DETAILS HP3442

Fax: (03) 479 7150Phone: (03) 479 7247

Sex:

* The appearance of a possible safety issue in this scheme does not mean Medsafe and CARM have concluded that this medicine causes the reaction

44 Prescriber Update 2016; 37(3) September

Beta-lactam Antibiotics and Cross-reactivityKey Messages

z Cross-reactivity occurs between beta-lactams with a closely related structure and affects antibiotic choice in allergic patients.

z The beta-lactam ring, the thiazolidine/dihydrothiazine ring and the side-chains are all potentially immunogenic.

z Cross-reactivity between penicillin and third-generation cephalosporins occurs in 2% to 3% of penicillin-allergic patients.

z Cross-reactivity may be much higher for beta-lactams with a side chain that is similar or identical.

z Allergy test results are useful when positive, but a negative result does not adequately exclude allergy to the specific antibiotic.

Allergy to Beta-lactam AntibioticsPatients commonly report an allergy to penicillin, however reaction details are often vague and many patients may be incorrectly labelled ‘penicillin allergic’1,2.

Careful individual risk-benefit assessment is essential when considering the use of a beta-lactam antibiotic, taking into consideration details of the history of the prior reaction and allergy test results3,4.

In addition, consideration should be given to the structure of the beta-lactam antibiotic that was responsible for the reaction. Cross-reactivity occurs between beta-lactams with a closely related structure and affects antibiotic choice.

Beta-lactam Antibiotic Structure and Degradation PatternThe basic structure of all beta-lactam antibiotics consists of a four-membered beta-lactam ring (Figure 1). In addition to the four-membered beta-lactam ring:

� penicillins have a thiazolidine ring and a single side-chain that differs for each type of penicillin

� cephalosporins have a dihydrothiazine ring and two side-chains instead of one

� carbapenems have a slightly different thiazolidine ring structure to penicillin

� aztreonam, a monobactam, has a beta-lactam ring with no adjacent ring.

The beta-lactam ring, the thiazolidine/dihydrothiazine ring and the side-chains are all potentially immunogenic4,5.

Despite their similar structure, penicillins and cephalosporins differ in their degradation pattern. Penicillins break down to form the stable penicilloyl moiety and a range of reactive intermediates. These derivatives have the potential to elicit an immune response4,6. In contrast, the degradation of cephalosporins involves the rapid fragmentation of the structural rings and the degradation products are less immunogenic.

Figure 1: Basic chemical structures of beta-lactam antibiotics showing differences in ring structure and number of side chains (R)6

Cross-reactivity between Beta-lactamsIndividuals with an allergy to one beta-lactam antibiotic may react to other structurally similar beta-lactams. Cross-reactivity between penicillin and first- and early (pre-1980) second-generation cephalosporins has been reported to occur in up to 10% of penicillin allergic patients. However, older studies may have overestimated the degree of cross-reactivity as the early cephalosporins contained traces of penicillin4,7. Cross-reactivity between penicillin and third-generation cephalosporins occurs in 2% to 3% of penicillin-allergic patients4,5,8,9. The degree of cross-reactivity may be much higher for beta-lactams with similar or identical side-chains4,5.

Clinical cross-reactivity among cephalosporins mainly relates to the side-chains4. However, it should be noted that cephalosporins cause immune-mediated reactions in 1% to 3% of patients even in the absence of a history of

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Prescriber Update 2016; 37(3) September 45

penicillin allergy. Therefore, administration of a cephalosporin with different side-chains may still result in an allergic response due to co-existing sensitivities4,5,10.

Allergy Testing to Beta-lactam AntibioticsIf a patient has a convincing history of an immediate hypersensitivity reaction or a severe cutaneous adverse reaction to a specific antibiotic, allergy testing is not required for confirmation and the antibiotic concerned should be avoided2. Allergy testing is mainly limited to immediate, IgE-mediated hypersensitivity3.

A blood test for specific IgE to penicillins is available, but does not include all antigenic determinants. A positive test result is highly predictive of penicillin allergy, but a negative result does not adequately exclude penicillin allergy4,11.

Skin testing for allergy to beta-lactams is a specialist procedure and is only offered at certain hospitals2. Approximately one-third of patients with a true penicillin allergy have a negative skin test. Therefore, a negative skin test does not adequately exclude allergy4.

If a patient reacts to a specific cephalosporin, skin testing to another cephalosporin with a different side chain may be considered. If skin testing is negative, graded oral challenge with the alternative cephalosporin, under specialist supervision, may be considered4.

Further information on beta-lactam allergy testing in New Zealand can be found on the Best Practice Advocacy Centre (BPAC) website (www.bpac.org.nz/bpj/2015/june/allergy.aspx).

Further information on the management of patients with beta-lactam antibiotic allergies,

including tables of beta-lactam antibiotics that share similar or identical side chains, can be found in the guidance prepared by The Standards of Care Committee of the British Society for Allergy and Clinical Immunology (BSACI)8.

References1. Macy E. 2014. Penicillin and beta-lactam allergy:

epidemiology and diagnosis. Current Allergy and Asthma Reports 14(11): 476.

2. Best Practice Advocacy Centre (BPAC). 2015. When is an allergy to an antibiotic really an allergy? Best Practice Journal 2015(68): 22.

3. Australasian Society of Clinical Immunology and Allergy. 2014. Antibiotic Allergy Clinical Update. URL: www.allergy.org.au/images/stories/hp/info/ASCIA_HP_Clinical_Update_Antibiotic_Allergy_2014.pdf (accessed 21 July 2016).

4. Mirakian R, Leech SC, Krishna MT, et al. 2015. Management of allergy to penicillins and other beta-lactams. Clinical & Experimental Allergy: Journal of the British Society for Allergy and Clinical Immunology 45(2): 300–327.

5. Romano A, Gaeta F, Arribas Poves MF, et al. 2016. Cross-Reactivity among Beta-Lactams. Current Allergy and Asthma Reports 16(3): 24.

6. Khan DA, Solensky R. 2010. Drug allergy. Journal of Allergy and Clinical Immunology 125(2 Suppl 2): S126–137.

7. Pichichero ME. 2005. A review of evidence supporting the American Academy of Pediatrics recommendation for prescribing cephalosporin antibiotics for penicillin-allergic patients. Pediatrics 115(4): 1048–1057.

8. Madaan A, Li JT. 2004. Cephalosporin allergy. Immunology and Allergy Clinics of North America 24(3): 463–476, vi-vii.

9. Pichichero ME. 2007. Use of selected cephalosporins in penicillin-allergic patients: a paradigm shift. Diagnostic Microbiology and Infectious Disease 57(3 Suppl): 13S–18S.

10. Pichichero ME, Zagursky R. 2014. Penicillin and cephalosporin allergy. Annals of Allergy, Asthma & Immunology 112(5): 404–412.

11. Joint Task Force on Practice Parameters. 2010. Drug Allergy: An Updated Practice Parameter. Annals of Allergy, Asthma & Immunology 105: 259–293.e278.

Medicines can Impair DrivingKey Messages

z It is against the law to drive while impaired.

z Warn patients taking medicines that may impair their driving ability of potential effects and encourage them to discuss any concerns.

z Symptoms of impairment include sedation, blurred vision or inability to focus, as well as feeling manic or overconfident.

It is against the law to drive while impaired. The Land Transport Amendment Act 2009 states that it is an offence to drive while impaired and with evidence in the bloodstream of a qualifying drug1. Qualifying drugs include controlled drugs and prescription medicines. Further information on the legislation is available at www.transport.govt.nz/legislation/acts/QAsdrugimpaireddrivinglaw

Healthcare professionals can assist their patients by informing them of the potential impairing effects of medicines (this includes over-the-counter and pharmacist-only medicines as well

46 Prescriber Update 2016; 37(3) September

as prescription medicines). Medicines with the potential to impair driving ability include some pain relievers, anxiolytics, antidepressants, sleeping aids, antiepileptics, sedating antihistamines, antipsychotics, medicines used in the eyes, cough and cold medicines and some heart medicines2.

Not every medicine within each medicine class will impair driving nor cause impairment in every person. However, patients should be informed of the potential risk. Additionally, it is important for patients to continue treatment as some conditions requiring medical treatment may themselves affect driving ability if left untreated3.

Symptoms of impairment include dizziness, drowsiness, headache, nausea, blurred vision, slowed reactions, inability to focus, being easily confused, slurred speech and feeling manic or overconfident2. Importantly, the patient may not always be aware that they are impaired and impairment may continue the following day (eg, zopiclone and next-day impairment, see the Prescriber Update article for more information www.medsafe.govt.nz/profs/PUArticles June2014ZopicloneAndNext DayImpairment.htm).

Further guidance to patients could include:2,3

� not driving until the patient knows how the medicine affects them

� avoiding driving completely, particularly during treatment of a short-term condition

� not driving if the patient experiences any symptoms as described above

� considering alternative options, such as a different medicine or if it can be taken at a different time of day.

Please note that this information is advisory only. Data sheets for individual medicines should be checked for information on possible driving effects. Medicine data sheets are available at www.medsafe.govt.nz/profs/Datasheet/DSForm.asp

References1. Land Transport Amendment Act 2009. URL: www.legislation.

govt.nz/act/public/2009/0017/40.0/DLM2014 902.html (accessed 11 July 2016).

2. NZ Transport Agency. Are you safe to drive? URL: www.nzta.govt.nz/safety/driving-safely/medication/are-you-safe-to-drive/ (accessed 11 July 2016).

3. Medicine and Healthcare product Regulatory Agency (MHRA). Drug Safety Update – Drugs and driving: blood concentration limits set for certain drugs. 16 February 2015. URL: www.gov.uk/drug-safety-update/drugs-and-driving-blood-concentration-limits-set-for-certain-drugs (accessed 11 July 2016).

MARC’s Remarks: June 2016 MeetingThe Medicines Adverse Reactions Committee (MARC) met on 29 June 2016 to discuss a number of medicine-related safety issues.

T h e M A RC d i s c u s s e d t h e u s e o f dexchlorpheniramine and other sedating antihistamines in children. The MARC recommended that the use of sedating antihistamines should be restricted according to age and indication as follows.

� Contraindicated in children under two years of age for all indications.

� Remain contraindicated in children under six years of age for the treatment of cough and colds.

� Contraindicated in children under 12 years of age for the treatment of insomnia.

� Available as prescription medicines when used in children under six years of age for nausea and vomiting and for travel sickness.

The MARC reviewed the current sedation warning and available evidence on the sedating

effects of loratadine- and desloratadine-containing products. The MARC considered that a warning should remain for these non-sedating antihistamines but be amended to reflect the low risk of sedation.

The MARC reviewed the available evidence around the use of tramadol in children. The MARC recommended that Medsafe request the sponsors of tramadol-containing products to add a contraindication in children under two years of age and update the warnings and precautions section of the medicine data sheets.

The MARC reviewed the available information on the risks of chronic kidney disease and dementia with proton pump inhibitors. The MARC concluded that the evidence was insufficient to support an association for either of these risks.

Read further information on the 166th meeting held on 29 June 2016 at www.medsafe.govt.nz/profs/adverse/Minutes166.htm

Prescriber Update 2016; 37(3) September 47

New Medicine ApprovalsFor the period 16 April to 15 July 2016.

Trade Name (Active Ingredient)

Dose Form and Strength

Therapeutic Area

Alacare (aminolevulinic acid)

Dermal patch 8 mg

Actinic keratosis lesions on the face and scalp

Daklinza (daclatasvir)

Tablet30 mg

Chronic hepatitis C virus (HCV) infection

Duavive (bazedoxifene/ conjugated estrogens)

MR tablet0.45 mg/20 mg

Oestrogen deficiency symptoms in postmenopausal women with a uterus

Esbriet(pirfenidone)

Capsule 267 mg

Idiopathic pulmonary fibrosis

Mirvaso(brimonidine)

Topical gel3.3 mg/g

Rosacea

Opdivo(nivolumab)

Concentration for infusion100 mg/10 mL and 40 mg/4 mL

Unresectable (Stage III) or metastatic (Stage IV) melanomaAdvanced or metastatic squamous or non-squamous non-small cell lung cancer (NSCLC)

Simbrinza(brimonidine/ brinzolamide)

Eye drops suspension1%/0.2%

Open-angle glaucoma or ocular hypertension

Sunvepra (asunaprevir)

Capsule100 mg

Chronic HCV infection

Visanne (dienogest)

Tablet 2 mg

Endometriosis

VPRIV (velaglucerase alpha)

Powder for infusion400 units

Type I Gaucher disease

Abbreviations: FC film coated, MR modified release

A full description of each product can be found in individual medicine data sheets at www.medsafe.govt.nz/profs/Datasheet/dsform.asp

48 Prescriber Update 2016; 37(3) September

Prescriber Update is a member of the

Medsafe New Zealand Medicines and Medical Devices Safety Authority

A business unit of the Ministry of Health

Editor Richard Perry Medsafe, PO Box 5013, Wellington, New ZealandPh: (04) 819 6800, Fax: (04) 819 6806E-mail: medsafeadrquery@moh.govt.nz

Editorial TeamRowan Pollock, Acting Manager, Clinical Risk

Dr Susan Kenyon, PhD, Principal Technical Specialist, Pharmacovigilance

Lily Chan, Advisor Pharmacovigilance

Jo Prankerd, Advisor Pharmacovigilance

Dr Geraldine Hill, Senior Medical Advisor

Acknowledgements Derek Fitzgerald

Desiree Kunac

Dr Samantha Stubbs

Dr Peter Jones

Clinical AdvisorDr Geraldine Hill

Acting Group ManagerChris James

Prescriber Update is published and distributed by Medsafe in the interests of safer, more effective use of medicines and medical devices.

Medsafe also acknowledges the contribution of the New Zealand Pharmacovigilance Centre in providing data and advice for articles.

An electronic version of Prescriber Update is available at www.medsafe.govt.nz/profs/PUarticles.asp

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Data sheets, consumer medicine information, media releases, medicine classification issues and adverse reaction forms can be found at www.medsafe.govt.nz

Published with the permission of the Director-General of Health.

The copyright owner of this publication is the Ministry of Health, which is part of the New Zealand Crown. Information about copyright requirements available at www.health.govt.nz/copyright